Project Summary: Wnt signaling plays a critical role in maintenance, activation and lineage commitment of skin somatic stem cells (SSCs). Although accumulating evidence unveils the significance of cytoskeleton and motor proteins in skin development, tissue homeostasis and wound repair, it remains unclear how cytoskeletal dynamics transmit the niche signaling to regulate the Wnt pathway in skin SSCs. Understanding this process is of fundamental importance because defects in the Wnt pathway lead to various skin diseases including cancer. In searching for potential cytoskeletal regulators involved in this process, we found that a mammalian spectraplakin protein, ACF7 (Actin Crosslinking Factor 7), is highly enriched in skin SSCs. Our preliminary results revealed a critical function of ACF7 and its paralog BPAG1 (Bullous Pemphigoid Antigen 1) in coordinating cytoskeletal dynamics and transmitting the Wnt signals in skin SSCs. In this proposal, we will take the advantages of our extensive expertise in skin SSCs to perform a combinatorial study encompassing in vivo characterization of ACF7 and BPAG1 mutant animals and in vitro investigation of the underlying cellular and molecular mechanisms. In particular, we will test a central hypothesis that cytoskeletal dynamics controlled by ACF7 and BPAG1 regulate functions of skin SSCs via the Wnt signaling pathway. Data generated from the proposed experiments will greatly advance our understanding of the basic mechanisms underlying skin SSC behaviors. In addition, our study will potentially lead to the development of novel therapeutic treatments for diseases related to skin SSCs.